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We showed previously that amphetamine (AMPH)-evoked DA release is markedly impaired in rats depleted of insulin with the diabetogenic agent streptozotocin (STZ). Similarly, functional magnetic resonance imaging experiments revealed that the blood oxygenation level-dependent signal following acute AMPH administration in STZ-treated rats is reduced. Here, we report that these deficits are restored by repeated, systemic administration of AMPH (1.78 mg\/kg, every other day for 8 d). AMPH stimulates DA D<jats:sub>2<\/jats:sub>receptors indirectly by increasing extracellular DA. Supporting a role for D<jats:sub>2<\/jats:sub>receptors in mediating this \u201crescue,\u201d the effect was completely blocked by pre-treatment of STZ-treated rats with the D<jats:sub>2<\/jats:sub>receptor antagonist raclopride before systemic AMPH. D<jats:sub>2<\/jats:sub>receptors regulate DAT cell surface expression through ERK1\/2 signaling. In<jats:italic>ex vivo<\/jats:italic>striatal preparations, repeated AMPH injections increased immunoreactivity of phosphorylated ERK1\/2 (p-ERK1\/2) in STZ-treated but not control rats. These data suggest that repeated exposure to AMPH can rescue, by activating D<jats:sub>2<\/jats:sub>receptors and p-ERK signaling, deficits in DAT function that result from hypoinsulinemia. Our data confirm the idea that disorders influencing insulin levels and\/or signaling, such as diabetes and anorexia, can degrade DAT function and that insulin-independent pathways are present that may be exploited as potential therapeutic targets to restore normal DAT function.<\/jats:p>","DOI":"10.1523\/jneurosci.3759-11.2012","type":"journal-article","created":{"date-parts":[[2012,2,22]],"date-time":"2012-02-22T17:51:40Z","timestamp":1329933100000},"page":"2637-2647","source":"Crossref","is-referenced-by-count":38,"title":["Rescue of Dopamine Transporter Function in Hypoinsulinemic Rats by a D<sub>2<\/sub>Receptor\u2013ERK-Dependent Mechanism"],"prefix":"10.1523","volume":"32","author":[{"given":"W. 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